Small-molecule covalent inhibitors, also known as irreversible inhibitors, are a class of inhibitors that exert their biological functions by irreversible binding of covalent bonds to target protein residues. Covalent inhibitor drugs have made important contributions to human health over the past few decades. Relative to non-covalent inhibitors, covalent inhibitors enhance affinity to targets by covalent bonding to target proteins, which is the underlying cause of the high bioactivity of the covalent inhibitors. In recent years, due to generation of resistance to non-covalent targeting anti-tumor drugs, especially to a large number of kinase-targeted tinib drugs, people have paid more attention to covalent inhibitor drugs again. In recent years, many large pharmaceutical companies have developed covalent inhibitors for specific enzyme targets. Currently, some covalent inhibitors, including afatinib, canertinib, and neratinib, have entered clinical trials. Among them, Afatinib was officially approved by the US FDA on Jul. 12, 2013 for the treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation, becoming the first FDA-approved new irreversible inhibitor drug for treatment of lung cancer. In addition, antiviral covalent drugs have also been a research hotspot in recent years, and great progress has been made. For example, in 2011, FDA approved two anti-hepatitis C virus covalent inhibitory drugs, namely, Telaprevir and Boceprevir. These studies demonstrate that irreversible inhibitors are effective for the treatment of diseases.
Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signal kinase expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays a crucial role in the signaling pathways of B cells that link cell surface B-cell receptor (BCR) and stimulate the downstream cell responses. Btk is a key regulator, affecting B cell development, activation, signaling, and survival. In addition, Bkt plays a role in signaling pathways of numerous other hematopoietic cells, such as Toll like receptor (TLR)- and cytokine receptor-mediated TNF-α production in macrophages, Immunoglobulin E receptor (FccR1) signaling in mast cells, signaling for inhibition of Fas/APO-1 apoptosis in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. For example, see in C. A. Jeffries et al, J. Bio. Chem. (2003) 278: 26258-26264, N. J. Horwood et al, J. Exp.
Med. (2003) 197: 1603-1611. Recent studies have shown that the Btk signaling pathway is a new hotspot in the current clinical treatment researches of non-Hodgkin's lymphoma (NHL), especially chronic lymphocytic leukemia (CLL), B-cell lymphoma and autoimmune diseases. Small-molecule Btk inhibitors inhibit Btkautophosphorylation by binding to Btk by acting on the BCR signaling pathway, thereby preventing Btk activation and further blocking cell conduction and inducing apoptosis. The release of the Btk inhibitor, ibrutinib, has been considered as a “breakthrough” new drug by FDA, and its research and development prospects are broad. However, in recent year's treatment, it has gradually found that ibrutinib has bleeding-related side effects, and literature studies suggest that it may be related to the poor selectivity of ibutinib, especially the related activities of TEC kinases. In addition, in the FDA application documents of ibrutinib, some review experts stated that the IC50 of its hERG channel blocking activity is low (IC50=1 μM), and there is a risk of cardiac toxic and side effects. Therefore, there is an urgent need to develop a more efficient class of selective BTK inhibitors for the treatment of related diseases.
A class of BTK irreversible inhibitors and their optical isomers or pharmaceutically acceptable salts or solvates, are reported in the applicant's prior patent documents (Chinese Patent Application Nos.: 201510242552.8 and 201610286399.3), with I and II in the following formula as represent compounds. Through further research, we found a class of compounds with high kinase selectivity, low hERG inhibitory activity and BTK inhibitors with good pharmacokinetic properties, which are expected to further reduce the risk of bleeding, rash, cardiac toxic side effects and so on.
